The goal of this project is to understand the dysregulated cell growth that is fixed or imprinted on the synovium in rheumatoid arthritis (RA). In contrast to a large body of data on how proinflammatory cytokines impact synovial cells, the actions of nonhematopoietic and angiogenic growth factors in RA are poorly understood, despite their abundance in synovium. Among these factors FGF-1 is markedly over expressed in RA compared to non-inflammatory synovium and the known functions of FGF-1 (angiogenesis and mesenchymal proliferation) are the hallmarks of hyperplastic pannus that causes joint destruction in RA. Recent data support this concept by showing that fibroblasts protect RA T cells from undergoing apoptosis, as usually occurs, when they are removed from the synovium. Therefore, the RA synovium provides an FGF-1 rich environment that may link gene activation in T cells with the intense proliferation and migration of fibroblasts and vascular cells. Studies on the regulation and actions of FGF-1 in cultured synovial cells reveal several unanticipated outcomes. For example, most mesenchymal cells including human dermal fibroblasts, HUVECs and 3T3 cells respond to FGF-1 by vigorous proliferation; synovial cells, however, respond poorly to FGF-1 despite the presence of high affinity receptors. Further, proinflammatory cytokines (e.g. TNF, IL-1, IL-6) have no effect on the expression of FGF-1 in synovial cells, while the "immunosuppressive" cytokine TGFbeta1 plays a key role in inducing FGF-1 production and in the outcome of receptor signaling. In addition, data show that in contrast to its expected antiproliferative effect, TGFbeta synergies with FGF-1 to produce a robust mitotic response even in the absence of serum. This synergy between TGBbeta and FGF-1 is not found in synovial cell lines derived from OA patients or from normals but this phenotype is highly reproducible in RA synoviocytes. In addition, FGF-1 induces gene transcription from an AP-1 promoter (collagenase) only in RA synoviocytes while AP-1 transcription is not activated by the actions of FGF-1 on synovial cells from normal individuals. Cellular correlates of FGF-1 actions are seen as persistent nuclear or perinuclear translocation of FGF-1 in RA synoviocytes but not in synovial cells from normal subjects. These observations suggest that the unchecked production of FGF-1 and its aberrant synergy with TGFbeta1 are linked to alterations in signal transduction and gene expression which are imprinted on RA synoviocytes. Therefore this project will first, identify signal transduction and gene activation pathways that reprogram rheumatoid synoviocytes for a synergistic response to FGF-1 and TGFbeta, and then investigate how these events are coupled to receptor interactions and the intracellular fate of FGF-1. To test the hypothesis that multiple cell types in the synovium may be reprogrammed with an altered growth phenotype, we will extend these studies and examine the molecular programming of endothelial cells from RA synovium. The approaches employed are designed to identify new targets for intervention in progressive joint destruction and a novel technique using cell permeable peptides will be tested in these studies. These studies are relevant not only to understanding progressive joint destruction in RA but are also of importance to a variety of disorders characterized by fibroproliferation including pulmonary fibrosis, interstitial nephritis, and chronic allograft rejection. The project will also provide information on how to utilize the immunomodulatory actions of TGFbeta without its unwanted fibroproliferative actions.